AML is the most frequent type of adult leukemia and the second most common pediatric leukemia and remains one of the most difficult to cure, with most studies reporting long-term cure rates of 30-40%. Activating somatic mutations of the FLT3 gene in patients with AML have been discovered in the past few years. These mutations are the most frequent genetic aberration in AML and portend a worse prognosis for patients expressing them. Though the mutations occur in different parts of the FLT3 gene, they are all characterized by constitutive activation of the tyrosine kinase domain of FLT3. This presents an excellent target for the development of novel therapeutics that might improve the chance of cure for these patients. We have spent the past several years proving that constitutive activation of FLT3 can transform cell lines and, when expressed in primary cells, results in myeloproliferative disease. We showed that inhibition of FLT3 resulted in cytotoxicity in modeled cell lines, leukemic cell lines and primary human AML samples. Most recently, we developed high-throughput cell-based assays that enabled us to screen thousands of small molecules for their ability to inhibit FLT3 in a highly potent and selective manner. This has now led to a clinical trial of FLT3 inhibitors in AML patients with FLT3 activating mutations at Johns Hopkins that will also be opened soon at the M.D. Anderson Cancer Center. This gives us the opportunity to test hypotheses related to the mechanisms of response, resistance and synergy with chemotherapy for this class of agents, Our specific aims are: Specific Aim 1: Determine the extent and efficacy of FLT3 inhibition by CEP-701 in clinical trial patients with AML expressing FLT3 activating mutations. Specific Aim 2: Determine some of the mechanisms involved in resistance to CEP-701-mediated cytotoxicity in FLT3/ITD mutant trial patients. Specific Aim 3: Utilize primary leukemic blasts from patients with AML expressing FLT3 mutations to establish the optimal combinations of chemotherapy to use with FLT3 inhibitors for future clinical trials. These studies will improve the outcome of AML patients with FLT3 mutations who currently have a very poor prognosis.